The overall objective of this research program is to develop a fish model for the investigation of hepatic copper metabolism in order to advance our understanding of the molecular kinetics of copper in eukaryotic cells. Copper is a highly toxic metal and alterations in its normal metabolism result in severe cellular dysfunction, such as expressed in Wilson's disease. The white perch (Morone americana) accumulates exceptionally high copper concentrations in the liver (greater than 1000 Mug/g wet weight) under conditions of natural exposure. These levels are greatly in excess of hepatic copper concentrations observed in Wilson's disease patients. A closely related fish species, the striped bass (Morone saxatilis), exhibits hepatic copper levels similar to mammals and will serve as controls. The specific aim of this project is to determine the mechanisms which account for the abnormal accumulation of copper in white perch. Experimental studies using isolated hepatocytes and purified membrane preparations from these two fish species will investigate the role of membrane transport and intracellular protein binding in copper accumulation. A unique feature of this study is that the two fish species can be crossbred to produce hybrids which will allow us to investigate the genetic control of the accumulation factors. It is expected that this fish model will contribute new knowledge concerning the mechanisms which control copper kinetics in eukaryotic cells.